Phenethanolamine derivatives, compositions, and their use as agonists at atypical beta-adrenoreceptors

ABSTRACT

The present invention disclosed compounds of Formula I. The present invention also discloses beta-3 agonists of formula I and methods for treating beta-3 mediated diseases and condition using the compounds of formula I, in particular methods for treating diabetes or obesity.

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/US01/49299 Dec. 17, 2001, which claims priority from 0102408.2 filedJan. 31, 2001.

FIELD OF THE INVENTION

This invention relates to a new class of chemical compounds and to theiruse in medicine. In particular, the invention concerns novelphenethanolamine derivatives, methods for their preparation,pharmaceutical compositions containing them and their use as agonists ata typical beta-adrenoceptors (also known as beta-3-adrenoceptors).

BACKGROUND OF THE INVENTION

A typical beta-adrenoceptors belong to the family of adrenoceptors thatmediate the physiological actions of the hormones adrenaline andnoradrenaline. Such receptors have been described for example by J R SArch et. al., Nature, 309, 163–165 (1984); C Wilson et. al., Eur. J.Pharmacol., 100, 309–319 (1984); L J Emorine et. al., Science, 245,1118–1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100,831–839 (1990).

Phenethanolamine derivatives having activity at a typicalbeta-adrenoceptors are disclosed in, for example, European PatentApplications EP-A-0455006 and EP-A-0543662.

Sub-types of the adrenoceptors, α₁-, α₂-, β₁-, β₂- and β₃-(atypical) canbe identified on the basis of their pharmacological properties andphysiological effects. Chemical agents that stimulate or block thesereceptors (but not β₃) are widely used in clinical medicine. Morerecently, emphasis has been placed upon specific receptor selectivity inorder to reduce side effects caused, in part, by interactions with otherreceptors.

Atypical beta-adrenoceptors are known to occur in adipose tissue and thegastrointestinal tract. Atypical beta-adrenoceptor agonists have beenfound to be particularly useful as thermogenic anti-obesity agents andas anti-diabetic agents. Compounds having atypical beta-adrenoceptoragonist activity have also been described as being useful in thetreatment of hyperglycaemia, as animal growth promoters, as bloodplatelet aggregation inhibitors, as positive inotropic agents and asantiatherosclerotic agents, and as being useful in the treatment ofglaucoma.

SUMMARY OF THE INVENTION

The invention therefore provides, in a first aspect, compounds offormula (I) and pharmaceutically acceptable derivatives thereof:

wherein X is oxygen or sulfur, and where the heterocycle containing X issubstituted meta or para to the depicted NH;

-   R¹ is hydrogen or C₁₋₆alkyl;-   R represents substituents selected from C₁₋₆ alkyl, halogen,    trifluoromethyl and C₁₋₆alkoxy; and-   n represents an integer from 0–4.

Preferably the compounds of this invention are agonists for human beta-3adrenoceptor (“β₃”). More preferably, the compounds of this inventionare selective agonists for β₃.

In another aspect, the present invention provides a pharmaceuticalformulation comprising a compound of the invention. Preferredpharmaceutical compositions further comprise a pharmaceuticallyacceptable carrier.

In another aspect, the present invention provides a method for theprevention or treatment of clinical conditions or diseases susceptibleto amelioration by administration of an a typical beta-adrenoceptoragonist, comprising administration of an effective amount of a compoundor composition of this invention.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, in the manufacture of a medicament for the treatment ofconditions or diseases susceptible to amelioration by administration ofan a typical beta-adrenoceptor agonist.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms ‘alkyl’ and “alkoxy” mean a straight orbranched alkyl group or alkoxy group respectively, containing theindicated number of carbon atoms. For example, C₁₋₆alkyl means astraight or branched alkyl containing at least 1 and at most 6 carbonatoms.

Preferably the heterocycle containing X is substituted meta to thedepicted NH.

Preferably R¹ is hydrogen or methyl. When R¹ is other than hydrogen,then preferably the stereochemisty around the carbon to which R¹ isbonded is R.

Preferably R is chlorine, fluorine, or CF₃.

Preferably n is 0, 1, or 2. Most preferably n is 0.

Preferably the stereochemisty around the carbon to which the depicted OHis bonded is R.

It will be appreciated that the above compounds of Formula (I) maycontain optically active centers. The individual, isolated isomers andmixtures thereof, including racemates, are all within the scope of thepresent invention. Typically, where R¹ is methyl, mixtures ofdiastereomers of compounds of Formula (I) may be obtained, which areenriched with greater than or equal to 80% by weight of onediastereomer.

Suitable compounds of formula (I) of the invention include:

-   2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylic    acid;-   2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylic    acid;-   2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylic    acid;-   2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylic    acid;-   2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylic    acid;-   2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylic    acid; and pharmaceutically acceptable derivatives thereof.

Particularly preferred compounds of the invention include:

-   2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylic    acid;-   2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylic    acid; and pharmaceutically acceptable derivatives thereof.

By “a pharmaceutically acceptable derivative” is meant anypharmaceutically acceptable salt, ester, or salt of such ester, of acompound of formula (I) or any other compound which, upon administrationto the recipient, is capable of providing (directly or indirectly) acompound of formula (I) or an active metabolite or residue thereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be modified to provide pharmaceutically acceptablederivatives thereof at any of the functional groups in the compounds offormula (I). Of particular interest as such derivatives are compoundsmodified at the carboxyl function, hydroxyl functions or at aminogroups.

It will be appreciated by those skilled in the art that thepharmaceutically acceptable derivatives of the compounds of formula (I)may be derivatised at more than one position.

Preferred pharmaceutically acceptable derivatives of the compounds offormula (I) are pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts of the compounds of formula (I)include those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric,maleic, phosphoric, glycollic, lactic, salicylic, succinic,toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic,benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids.Other acids such as oxalic, while not in themselves pharmaceuticallyacceptable may be useful in the preparation of salts useful asintermediates in obtaining compounds of the invention and theirpharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal (e.g. sodium),alkaline earth metal (e.g. magnesium), ammonium and NR₄ ⁺ (where R isC₁₋₄alkyl) salts.

The compounds of formula (I) and their pharmaceutically acceptablederivatives act as agonists at a typical beta-adrenoceptors and as suchare useful in the treatment of clinical conditions susceptible toamelioration by administration of an a typical beta-adrenoceptoragonist. Such conditions include hyperglycaemia, obesity, hyperlipemia,irritable bowel syndrome and its associated pain, motility dysfunction,excessive gastrointestinal secretion, non-specific diarrhoea, neurogenicinflammation, regulation of intraocular pressure, triglyceridemia,diabetes, e.g. non-insulin-dependent diabetes mellitus (NIDDM or Type2), such as obese NIDDM and non-obese NIDDM, diabetic complications suchas retinopathy, nephropathy, neuropathy, cataracts, coronary heartdiseases and arteriosclerosis, osteoporosis; and gastrointestinaldisorders, particularly inflammatory gastrointestinal disorders. Theyare also of use in increasing the high-density-lipoprotein (HDL)cholesterol concentration and decreasing the triglyceride concentrationin blood serum, especially human blood serum, and are therefore ofpotential use in the treatment and/or prophylaxis of atherosclerosis.They also may be useful for the treatment of hyperinsulinaemia,depression, muscle wasting, and urinary incontinence. References in thisspecification to treatment include prophylactic treatment as well as thealleviation of symptoms.

In a further aspect, the invention provides the use of a compound ofgeneral Formula (I) or a pharmaceutically acceptable salt or solvatethereof, for the manufacture of a medicament for the treatment of acondition susceptible of amelioration by an a typical beta-adrenoceptoragonist.

While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical it is preferable topresent the active ingredient as a pharmaceutical formulation. Theinvention thus further provides a pharmaceutical formulation comprisinga compound of Formula (I) or a pharmaceutically acceptable derivativethereof together with one or more pharmaceutically acceptable carriersthereof and, optionally, other therapeutic and/or prophylacticingredients. The carrier(s) or excipient(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand not deleterious to the recipient thereof.

The compounds for use according to the present invention may beformulated for oral, buccal, parenteral, rectal or transdermaladministration or in a form suitable for administration by inhalation orinsulation (either through the mouth or the nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavoring,coloring and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds according to the present invention may be formulated forparenteral administration by injection e.g. by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form e.g. in ampoules or in multi-dose containers, with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds according to the present invention may also be formulatedin rectal compositions such as suppositories or retention enemas, e.g.containing conventional suppository bases such as cocoa butter or otherglycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously,transcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compounds according to the present invention maybe formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

Suitable therapeutic ingredients which may be formulated with compoundsof the invention, together with one or more pharmaceutical carriers orexcipients, include ingredients which may be used in the same clinicalconditions as those listed herein for atypical beta-adrenoceptoragonists. Such ingredients may include, for example, PPAR-gammaagonists.

A proposed dose of the compounds according to the present invention foradministration to a human (of approximately 70 kg body weight) is 0.1 mgto 1 g, preferably to 1 mg to 100 mg of the active ingredient per unitdose, expressed as the weight of free base. The unit dose may beadministered, for example, 1 to 4 times per day. The dose will depend onthe route of administration. It will be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand weight of the patient as well as the severity of the condition to betreated. The precise dose and route of administration will ultimately beat the discretion of the attendant physician or veterinarian.

The compounds of the invention may be prepared by any of the processesknown in the art for the preparation of similar compounds. For example,according to a first process wherein X, R¹, and R are as defined as forformula (I), compounds of formula (I) may be prepared by reaction ofcompounds of formula

(II) and (III)

-   where P¹ and P² are suitable protecting groups for oxygen and    nitrogen groups respectively and R² is lower alkyl or H, in the    presence of a reducing agent, followed by deprotection of any    protecting groups present.

Compounds of formula (II) are described in PCT publication numberWO95/33724 or may be prepared by standard methods.

In an alternative process, a compound of formula (I) may be prepared byhydrolysis of a compound of formula (IV) or a pharmaceuticallyacceptable version thereof:

wherein R and R¹ are as defined in formulas (II) and (III), R² is loweralkyl and R³ represents C₁₋₆ alkyl or aryl optionally substituted byhydrogen, C₁₋₆ alkyl or halogen; followed by the step of hydrolysing theester group —CO₂R² to produce a compound of formula (I), wherein thefuran ring is substituted by a —CO₂H group.

Preferably, hydrolysis of a compound of formula (IV) to form a compoundof Formula (I) is carried out by reflux in the presence of an aqueoussolution of a group 1 or group 2 metal hydroxide, e.g. NaOH or KOH, andpreferably an alkanol, e.g. MeOH, for at least 4 h. The step ofhydrolysing the ester group —CO₂R² to produce a compound of formula(IA), wherein R⁴ is substituted by a —CO₂H group can be carried out by afurther hydrolysis step under standard hydrolysis conditions as would beapparent to a skilled person.

A compound of formula (IV) may be prepared by reacting a compound offormula (V) with a compound of formula (VI):

at elevated temperature and pressure, optionally in the presence of oneor more of: C₃₋₆alkanols, acetonitrile, N-methyl-pyrrolidinone (NMP),isobutylacetate, isopropylacetate, dimethylformamide (DMF), toluene,xylene or dimethylacetamide (DMA); preferably toluene and/or xylene. Thetemperature for the reaction is suitably 100° C. or greater, preferably100–150° C., more preferably 100–120° C.

The reaction of a compound of formula (V) with a compound of formula(VI) to form a compound of formula (IV) and the subsequent conversion ofa compound of formula (IV) to a compound of formula (I) may be carriedout separately or in situ. The reaction is preferably carried out insitu.

A compound of formula (VI) may be prepared from a compound of formula(VII):

wherein L represents a leaving group such as a halogen atom (e.g.chlorine), by cyclisation in the presence of a solvent selected from:dichloromethane (DCM), EtOAc, toluene and/or xylene, and a base selectedfrom: Na₂CO₃, NaOH, anhydrous Et₃N and/or an amine, e.g. aqueous NH₃.Preferably the solvent is DCM. Preferably the base is aqueous NH₃.

Compounds of Formula (VII) may be prepared from compounds of Formula(III) using any suitable method for the preparation of amidines. Forexample, by condensation of a compound of Formula (VIII) wherein Lrepresents

a leaving groupas previously defined, in the presence of a solvent selected from: DCM,toluene, EtOAc, or CH₃CN, and PCl₅ or POCl₃. Preferably the solvent isEtOAc. Preferably PCl₅ is present.

A compound of formula (III) may be prepared by reaction of a compound offormula (IX)

where Y represents the diazonium salt N₂ ⁺, with a suitable 5-memberedheterocyclic ring of formula (X), followed by reduction of the nitrogroup using standard methods. Suitable compounds of formula (X) areknown or are prepared by standard methods. For example, where X isoxygen, thus forming a furan group, a compound of formula (III) may beprepared directly by reaction of a compound of formula (IX) where Yrepresents the diazonium salt N₂ ⁺ with a furan of formula (X), followedby reduction with standard methods. A compound of formula (IX) where Yrepresents the diazonium salt N₂ ⁺ may in turn be prepared from acompound of formula (IX) where Y=NH₂ by standard methods known in theliterature. Alternatively, a compound of formula (III) may be preparedfrom the reaction of a compound of formula (IX) where Y=Br, I ortriflate with a furan of formula (X) in the presence of a suitablepalladium catalyst and a suitable base followed by reduction of thenitro group under standard conditions. Suitable palladium catalystsinclude, but are not limited to,tetrakis(triphenylphosphine)palladium(0). Suitable bases include, butare not limited to KOAc. Use of the palladium catalyst Pd(PPh₃)₄ in thepresence of the base KOAc is preferred.

Compounds of formula (IX) are known compounds or may be prepared byprocesses well known in the art.

Suitable reducing agents of use in the reactions include hydrogen in thepresence of a catalyst, such as a noble metal catalyst, for examplepalladium, platinum or platinum oxide, Raney-nickel or hydride reducingagents such as borohydrides, for example sodium borohydride sodiumtriacetoxyborohydride or sodium cyanoborohydride. Suitable reactionconditions will be readily apparent to those skilled in the art and arefurther illustrated by the accompanying examples.

The protecting groups used in the preparation of compounds of formula(I) may be used in conventional manner. See for example ‘ProtectiveGroups in Organic Chemistry’ Ed. J. F. W. McOmie (Plenum Press 1973) or‘Protective Groups in Organic Synthesis’ by Theodora W Greene and P M GWuts (John Wiley and Sons 1991).

Conventional amino protecting groups may include for example aralkylgroups, such as benzyl, diphenylmethyl or triphenylmethyl groups; andacyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.

Conventional oxygen protecting groups may include for example alky silylgroups, such as trimethylsilyl, or tert-butyldimethylsilyl; alkyl etherssuch as tetrahydropyranyl, or tert-butyl; or esters such as acetate.

Removal of any protecting groups present may be achieved by conventionalprocedures.

Atypical beta-adrenoceptor agonists are compounds, which demonstrate apharmacological response mediated at atypical beta-adrenoceptors. Thisactivity has been measured as the ability to stimulate lipolysis by ratadipocytes at sub-micromolar concentrations, in a response that isresistant to blockade by standard beta-adrenoceptor blocking drugs suchas propranolol.

Another useful means of identifying an a typical beta-adrenoceptoragonist involves the measurement of agonist activity at a typicalbeta-adrenoceptors in the rat isolated lower oesophagus. Typically inthis assay, a compound of general Formula (I) for use according to thepresent invention has an equipotent molar ratio (EPMR) relevant toisoprenaline of less than 30. The rat oesophagus assay is based uponthat described by Ford et. al., Br. J. Pharmacol., 105(suppl.), 235P,1992. The relative potency of each test compound (EPMR) is compared toisoprenaline as follows:

${EPMR} = \frac{{EC50}\mspace{14mu}{agonist}}{{EC50}\mspace{14mu}{isoprenaline}}$wherein EC₅₀ is the molar concentration of agonist which produces 50% ofthe maximum possible response for that agonist.

A particularly useful method for determining agonist activity at human atypical beta-adrenoceptors involves the use of Chinese hamster ovarian(CHO) cells transfected with the human beta-3-adrenoceptor according toMethod 1. The cell lines may also be transfected with human beta-1- andbeta-2-adrenoceptor in a similar manner to provide a method ofdetermining the selectivity of the compounds of the invention at thethree receptors.

Method 1—Cell Culture

General cell culture guidelines are observed (Fershney, R. A. (1987)Culture of animal cells: A manual of basic technique. Wiley-Liss, Inc.,N.Y.). A standard cell culture incubator is used (37° C., 5% CO2 in air,95% relative humidity). H β₃CHO cells are grown in DMEM/F12 (withpyroxidine-HCl, 15 mM HEPES, L-glutamine), supplanted with 10%heat-inactivated FBS, 500 μg/ml G418, 2 mM L-glutamine, 100 unitspenicillin G and 100 μg streptomycin sulfate. One confluent flask ofcells is trypsinised and resuspended in the above medium at aconcentration of 30–40,000 cells/100 μl and plated into 96-well flatbottom plates. The cells are then used for assay within 18–24 hours.

The medium is aspirated from each well, and replaced with 180 μlDMEM/F12 with 500 mM IBMX. Antagonists, if required, are added at thisstage. The plate is then placed back in the incubator for 30 min. Drugsare then added to the wells (20 μl, 100× required final concentration)for 60 min. Responses were determined by measuring cAMP levels of a 20ul sample of extracellular media using a scintillation proximity basedradio-immunoassay (NEN Flashplates).

CHO-6CRE-luciferase cell lines which stably express hβ₃ receptors areseeded at 30,000 cells/well for 24 hr in DMEM/F12 containing 10% FBS.Media is removed from the cells and replaced with DMEM/F12 buffer (180μl) containing 300 mM IBMX and 1 mM ascorbic acid for 30 min prior toaddition of compound. Vehicle or agonist (20 μl) is added and incubatedat 37° C. for 60 minutes. At the end of the incubation period, samplesof extracellular media are removed for direct assay in cAMP Flashplates(NEN).

As used herein, a compound is considered to be an agonist for hβ₃ if thecompound stimulates the accumulation of extracellular cAMP withCHO-6CRE-luciferase cells expressing hβ₃. The compounds of thisinvention have an EC₅₀ of at most 10 nM at hβ₃. The relative potency ofa h₃ agonist may be compared to its potency for stimulating theaccumulation of extracellular cAMP with CHO-6CRE-luciferase cellsexpressing hβ₂ and hβ₁. The compounds of this invention are at least 100times more potent at hβ₃ than at hβ₂ or hβ₁.

The invention is further illustrated by the following intermediates andexamples. All temperatures are in degrees centigrade. Chromatography wascarried out on silica (Merck 9385) unless otherwise stated. HPLCcharacterization systems are labeled as follows:

System 1: (C18), using a 30–80% acetonitrile-water with 0.1%trifluoroacetic acid gradient mobile phase with detection by absorbanceat 254 nM.

System 2: (C18), using 1:4 acetonitrile-water containing trifluoroaceticacid (0.1%) and triethylamine (0.1%) mobile phase with detection byabsorbance at 254 nM.

System 3: (C18), using 30–100% acetonitrile-water containingtrifluoroacetic acid (0.1%) and triethylamine (0.1%) mobile phase withdetection by absorbance at 254 nM.

System 4: (C18), using 1:1 acetonitrile-water containing trifluoroaceticacid (0.1%) mobile phase with detection by absorbance at 254 nM HPLCretention times are expressed in minutes as t_(R).

Intermediate 1

2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester.

A solution of 2-(3-aminophenyl)furan-3-carboxylic acid methyl ester(0.31 g) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.63 g) in dichloromethane (9 mL) containing acetic acid (0.03 mL) wasstirred at room temperature for 30 min. The reaction mixture was cooledto 0° C. and sodium triacetoxyborohydride (0.30 g) was added. Themixture was stirred at room temperature for 18 h, washed with aqueoussodium bicarbonate solution, dried over magnesium sulfate, andconcentrat d under reduced pressure. The residue was chromatographed onsilica eluting with hexanes: ethyl acetate (9:1) to give the titlecompound as a yellow solid (0.523 g). C₃₄H₄₇N₂O₆ClSi: M+Na 665

Similarly Prepared Were:

Intermediate 2

2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]furan-3-carboxylicacid methyl ester as a colorless gum (1.15 g), C₃₃H₄₅N₂O₆ClSi: MH⁺ 629,from 2-(3-aminophenyl)furan-3-carboxylic acid methyl ester (742 mg) and{(tert-butoxycarbonyl)-[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-amino}acetaldehyde(1.17 g).

Intermediate 3

2-[4-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester as a brown oil (0.45 g), TLC hexane:ethyl acetate(1:1) R_(f)=0.65, from 2-(4-aminophenyl)furan-3-carboxylic acid methylester (0.22 g) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.45 g).

Intermediate 4

2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a yellow oil (0.383 g), TLC hexane:ethyl acetate(1:1) R_(f)=0.66, from 2-(3-aminophenyl)thiophene-3-carboxylic acidmethyl ester (0.30 g) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.56 g).

Intermediate 5

2-[3-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a colorless gum (1.15 g). C₃₃H₄₅N₂O₅ClSSi: MH⁺ 646,from 2-(3-aminophenyl)thiophene-3-carboxylic acid methyl ester (795 mg)and{(tert-butoxycarbonyl)[2R-(tert-butyl-dimethyl-silanyloxy)-2-(3-chloro-phenyl)-ethyl]-amino}-acetaldehyde(1.17 g).

Intermediate 6

2-[4-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester as a yellow oil (0.155 g), C₃₄H₄₇N₂O₅ClSSi: MH⁺ 659,from 2-(4-aminophenyl)thiophene-3-carboxylic acid methyl ester (0.17 g)and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(0.32 g).

Intermediate 7

2-(3-Nitrophenyl)furan-3-carboxylic acid

A solution of 3-nitroaniline (8.28 g) in concentrated hydrochloric acid(20 mL) was treated with sodium nitrite (4.2 g) in water (20 mL) at 0°C. The mixture was stirred for 10 min, and then filtered. To thefiltrate was added 3-furancarboxylic acid (6.05 g) in acetone (10 mL),followed by a solution of cupric chloride (2.4 g) in water (8 mL). Themixture was left to stand at room temperature for two days, poured intowater (200 mL), and stirred for two hours. The resulting solid wasdissolved in 10% sodium bicarbonate solution, and triturated with ethylaceate. The resulting aqueous solution was acidified with 1Nhydrochloric acid to precipitate a solid. Recrystallization of the solidfrom benzene gave the title compound as a brown solid (3.57 g).C₁₁H₇NO₅: MH⁺ 232

Similarly Prepared Were:

Intermediate 8

2-(4-Nitrophenyl)furan-3-carboxylic acid as a tan solid (1.52 g), n.m.r.(DMSO-d₆) δ values include 6.91 (s, 1H),7.96 (s, 1H), 8.27 (dd, 4H),13.09 (bs, 1H), from 4-nitroaniline (4.14 g) and 3-furancarboxylic acid(3.03 g).

Intermediate 9

2-(3-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (0.45 g),C₁₁H₇NO₄S: MH⁻ 248, from 3-nitroaniline (4.14 g) and3-thiophenecarboxylic acid (3.46 g).

Intermediate 10

2-(4-Nitrophenyl)thiophene-3-carboxylic acid as a tan solid (2.83 g),C₁₁H₇NO₄S: MH⁻ 248, from 4-nitroaniline (4.14 g) and3-thiophenecarboxylic acid (3.46 g).

Intermediate 11

2-(3-Nitrophenyl)furan-3-carboxylic acid methyl ester

A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid (1.2 g) inmethanol (200 mL) containing concentrated sulfuric acid (5 drops) washeated under reflux for 18 h. The reaction solution was evaporated todryness under reduced pressure to give the title compound as a yellowsolid (0.66 g). m.p.=93–94° C.

Similarly Prepared Were:

Intermediate 12

2-(4-Nitrophenyl)furan-3-carboxylic acid methyl ester as a yellow solid(1.15 g), m.p.=113–114° C., from 2-(4-nitrophenyl)furan-3-carboxylicacid (0.52 g).

Intermediate 13

2-(3-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as a whitesolid (0.31 g), C₁₂H₉NO₄S: MH⁻ 262, from2-(3-nitrophenyl)thiophene-3-carboxylic acid (0.45 g).

Intermediate 14

2-(4-Nitrophenyl)thiophene-3-carboxylic acid methyl ester as a whitesolid (1.0 g), n.m.r. (DMSO-d₆) δ values include 3.78 (s, 3H), 7.43 (d,1H), 7.64 (m, 1H), 7.72 (m, 2H), 8.21 (d, 1H), 8.33 (m, 1H), from2-(4-nitrophenyl)thiophene-3-carboxylic acid (1.5 g).

Intermediate 15

2-(3-Aminophenyl)furan-3-carboxylic acid methyl ester

A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid methyl ester (1.0g) in methanol (60 mL) containing 10% palladium on carbon (2.9 g) wasstirred under 1 atmosphere of hydrogen for 1 h. The reaction mixture wasthen filtered through Celite. Removal of the solvent at reduced pressuregave the title compound as a yellow solid (0.75 g). C₁₂H₁₁NO₃: M+Na+ 240

Similarly Prepared Were:

Intermediate 16

2-(4-Aminophenyl)furan-3-carboxylic acid methyl ester as a yellow solid(1.0 g), Assay Found: C 66.19; H 5.17; N 6.33%, C₁₂H₁₁NO₃ requires C66.35; H 5.10; N 6.45%, from 2-(4-nitrophenyl)furan-3-carboxylic acidmethyl ester (1.0 g).

Intermediate 17

2-(3-Aminophenyl)thiophene-3-carboxylic acid methyl ester as a brown oil(0.30 g), C₁₂H₁₁NO₂S: M+Na⁺ 255, from2-(3-nitrophenyl)thiophene-3-carboxylic acid methyl ester (0.30 g).

Intermediate 18

2-(4-Aminophenyl)thiophene-3-carboxylic acid methyl ester as a brown oil(0.17 g),

C₁₂H₁₁NO₂S: MH⁺ 234, from 2-(4-nitrophenyl)thiophene-3-carboxylic acidmethyl ester (0.70 g).

Intermediate 19

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester

2-[3-(2R-{tert-Butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester (0.523 g) was dissolved in 4N hydrochloric acid indioxane (5.0 mL), stirred at room temperature for 1 h and then dilutedwith diethyl ether (10 mL) to separate an oil. The oil waschromatographed on silica and eluting with ethyl acetate: methanol (9:1)to give the title compound as a red oil (0.19 g). C₂₃H₂₅N₂O₄Cl: MH⁺ 429

Intermediate 20

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester hydrochloride as a white solid (613 mg), C₂₂H₂₃N₂O₄Cl:MH⁺ 415, from2-[3-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester (1.15 g).Similarly Prepared Were:

Intermediate 21

2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester as a brown oil (0.19 g), TLC ethyl acetate: methanol(8:2) R_(f)=0.27, from2-[4-(2R-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}propylamino)phenyl]furan-3-carboxylicacid methyl ester (0.45 g).

Intermediate 22

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester as an range oil (0.086 g), C₂₃H₂₅N₂O₃ClS: MH⁺ 445,from2-[3-(2R-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester (0.383 g).

Intermediate 23

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester hydrochloride as a tan foam (1.15 g), C₂₂H₂₃N₂O₃ClS:MH⁺ 431, from2-[3-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]-amino}ethylamino)phenyl]thiophene-3-carboxylicacid methyl ester (1.65 g).

Intermediate 24

2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester as an orange oil (0.060 g), C₂₃H₂₅N₂O₃ClS: MH⁺ 445,from2-[4-(2R-{tert-butoxycarbonyl-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propylamino)phenyl]thiophene-3-carboxylicacid methyl ester (0.155 g).

Intermediate 25

Methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylateas a white foam (992 mg), C₃₄H₄₇N₂O₆SiCl: [MH⁺] 643, from2-(3-aminophenyl)furan-3-carboxylic acid methyl ester (700 mg) and{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilanoxy)-2-(3-chlorophenyl)ethyl]amino}propionaldehyde(1.26 g).

Intermediate 26

Methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]-N-ethylpropylamino}phenyl)furan-3-carboxylateas a white foam (331 mg), C₃₅H₅₁N₂O₆SiCl: [MH⁺] 671, from methyl2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxy-ethylamino]propylamino}phenyl)furan-3-carboxylate(429 mg) and acetaldehyde (47 mg).

Intermediate 27

Ethyl 2-(3-aminophenyl)-3-furoate hydrochloride

To a stirred solution of 1-bromo-3-nitrobenzene (50 g) and ethyl3-furoate (48.6 g) in toluene (500 mL) were added potassium acetate(36.4 g) and tetrakis(triphenylphosphine)palladium(0) (14.3 g). Themixture was heated at reflux for 66 hours, cooled to room temperature,and filtered through Celite (50 g). The filtercake was rinsed with ethylacetate (2×200 mL). The combined filtrate/rinse was concentrated to anoil. Methanol (500 mL) and 10% palladium on carbon (50% wet paste, 3.2g) were added. The mixture was stirred under an atmosphere of hydrogenuntil uptake ceased. The mixture was filtered through Celite (50 g), andthe filtercake was rinsed with ethyl acetate (200 mL). The combinedfiltrate/rinse was concentrated to an oil, and ethyl acetate (250 mL)was added. The solution was washed with water (100 mL). The organicphase was dried over sodium sulfate, filtered, and concentrated to anoil. Dichloromethane (50 mL) was added, and the resulting solution wasfiltered through a silica gel plug (100 g). The plug was rinsed withdichloromethane (2500 mL) to extract all ethyl2-(3-aminophenyl)-3-furoate hydrochloride. The combined filtrate/rinsewas concentrated to an oil, and methyl tert-butyl ether (250 mL) wasadded. To this stirred solution was slowly added 4.0 M HCl in dioxane(93 mL). After aging for 15 minutes at 0–5° C., the precipitate wascollected by filtration, washed with methyl tert-butyl ether (2×100 mL),and dried in vacuo at 45–50° C. to yield 46.8 g (71% th) of the titlecompound as a beige solid. 1H NMR (300 MHz, d6-DMSO) δ:7.90 (d, 1H),7.78 (m, 2H), 7.51 (t, 1H), 7.30 (d, 1H), 4.25 (q, 2H), 1.26 (t, 3H).

Intermediate 28

Ethyl 2-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]-3-furoate

N-(2-chloroethyl)acetamide (1.21 g) in ethyl acetate (10 mL) was addedover 10 min to a stirred suspension of phosphorus pentachloride (2.08 g)in ethyl acetate (2 mL) at 0° C. under nitrogen to give a clear palestraw solution. After 45 min at 0° C. toluene (12 mL) was added, andethyl 2-(3-aminophenyl)-3-furoate hydrochloride (1.78 g) was added inone portion into the above solution at 0–5° C. The mixture was stirredat 0–5° C. for 10 min and then allowed to warm up to 20° C. After 2 hformation of the amidine is essentially complete (HPLC ethyl2-(3-aminophenyl)-3-furoate hydrochloride <2% @ 220 nm, a/a). Themixture was cooled to 0–5° C., crushed ice (18 g) was added over 20 minto destroy phosphorus oxychloride. Ammonium hydroxide (28%, 6.49 mL) wasadded at a rate that the internal temperature was kept below 25° C. (ca.15 min). After 1 h at 20° C. additional ethyl acetate (12 mL) added tothe above mixture, the organic layer was separated, washed withdeionized water (2×12 mL), and concentrated under reduced pressure. Theresidue was dissolved in acetone (5 mL) and ethyl acetate (5 mL), andtreated with oxalic acid (0.72 g) at 40° C. for 30 min. After aging at<20° C. for at least 12 h, the precipitate was collected by filtration,washed with acetone (2×0.5 vol), and dried in vacuo at 45–50° C. toyield 1.9 g (73%) of white solid. ¹H NMR (400, d₆-DMSO) δ: 8.00 (s, 1H),7.92–7.90 (m, 2H), 7.64–7.55 (m, 2H), 6.90 (d, 1H), 4.32 (t, 2H), 4.22(q, 2H), 3.93 (t, 2H), 2.22 (s, 3H), 1.24 (t, 3H).

EXAMPLE 1

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid

To a solution of2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester (0.19 g) in 3:1 methanol: water (5.5 mL) was addedsolid lithium hydroxide monohydrate (0.185 g). The solution was stirredat room temperature for 18 h and concentrated at reduced pressure. Theresidue was chromatographed on silica eluting with chloroform: methanol:conc. ammonium hydroxide (10:5:1) to give the title compound as a tansolid (0.067 g). m.p.=184–186° C., HPLC system 1: t_(R) 11.19 min.

Similarly Prepared Were:

EXAMPLE 2

2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid as a white solid (317 mg), m.p.=250° C. (dec), C₂₁H₂₁N₂O₄Cl: [MH⁺]402. Assay Found C 62.65; H 5.21; N 6.91%, C₂₁H₂₁N₂O₄Cl₁ requires C62.92; H 5.28; N 6.99%, from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid methyl ester hydrochloride (613 mg).

In an alternative preparation, ammonium hydroxide (28%, 13 mL) was addedover 10 min to a mixture of ethyl2-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]-3-furoate (13.0 g),deionized water (104 mL), and toluene (104 mL). After 30 min stirring,the organic layer was collected, washed with deionized water (26 mL),and concentrated to ca. 30 mL to remove traces of water azetropically.(R)-3-Chlorostyrene oxide (5.17 g) was added, and the resultant washeated under nitrogen at 110 C. for at least 14 h. The mixture wascooled to ca. 50° C. 1M Sodium hydroxide aqueous solution (77.8 mL) andmethanol (39 mL) were added, and the apparatus was configured fordistillation. After ca. 1 h, the homogeneous solution obtained washeated at reflux (ca. 4 h) until the hydrolysis was complete (HPLCacetate <2% @ 220 nm, a/a). The mixture was cooled to <50° C.

Methanol (26 mL) and 1M hydrochloric acid (78 mL) were heated to ca. 50°C. The reaction mixture from above was added over 20 min, and theresultant slurry was cooled to <20° C. and aged for a further 30 min.The product was collected by filtration, washed with deionized water(2×26 mL), and dried in vacuo at 50° C. to yield 12.7 g (95%) of thetitle compound as an off-white solid.

EXAMPLE 3

2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxylethylamino]propylamino}phenyl)furan-3-carboxylicacid as a tan solid (0.059 g), HRMS C₂₂H₂₃N₂O₄Cl: MH⁺ calc 415.1425,found 415.1412 Δ=1.3 mmu, HPLC system 1: t_(R) 11.06 min., from2-(4-{2R-[2-(3-chlorophenyl)-2R-hydroxylethylamino]propylaminophenyl}furan-3-carboxylicacid methyl ester (0.19 g).

EXAMPLE 4

2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid as a tan solid (0.088 g), HRMS C₂₂H₂₃N₂O₃ClS MH⁺ calc 431.1196,found 431.1180 Δ=1.6 mmu, HPLC system 1: t_(R) 12.38 min., from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester (0.086 g).

EXAMPLE 5

2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid as a cream colored solid (296.8 mg), m.p.=275° C. (dec)C₂₁H₂₁N₂O₃ClS: [MH⁺] 417. Assay Found C 60.47; H 5.04; N 6.67%,C₂₁H₂₁N₂O₄Cl₁ requires C 60.50; H 5.08; N 6.72%, from2-(3-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester hydrochloride (1.15 g).

EXAMPLE 6

2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid as a tan solid (0.010 g), HRMS C₂₂H₂₃N₂O₃ClS MH⁺ calc 431.1196,found 431.1183 Δ=1.3 mmu, HPLC system 1: t_(R) 12.03 min., from2-(4-{2R-[2-(3-chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid methyl ester (0.060 g).

1. A compound of formula (I), or a pharmaceutically acceptablederivative thereof:

wherein X is oxygen or sulfur, and where the heterocycle containing X issubstituted meta or para to the depicted NH; R¹ is hydrogen orC₁₋₆alkyl; R represents substituents selected from C₁₋₆ alkyl, halogen,trifluoromethyl, and C₁₋₆alkoxy; and n represents an integer from 0–4.2. A compound of claim 1 wherein the heterocycle containing X issubstituted meta to the depicted NH.
 3. A compound of claim 1 wherein R¹is hydrogen or methyl.
 4. A compound of claim 1 wherein when R¹ is otherthan hydrogen, the stereochemisty around the carbon to which R¹ isbonded, is R.
 5. A compound of claim 1 wherein R is chlorine, fluorine,or CF₃.
 6. A compound of claim 1 wherein n is 0, 1, or
 2. 7. A compoundof claim 1 wherein n is
 0. 8. A compound of claim 1 wherein thestereochemisty around the carbon to which the depicted OH is bonded, isR.
 9. A compound of claim 1 wherein said compound is selected from thegroup consisting of2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)furan-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxylethylamino]propylamino}phenyl)furan-3-carboxylicacid;2-(3-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid;2-(4-{2R-[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]propylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.
 10. Acompound of claim 1 wherein said compound is selected from the groupconsisting of2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)furan-3-carboxylicacid;2-(3-{[2-(3-Chlorophenyl)-2R-hydroxyl-ethylamino]ethylamino}phenyl)thiophene-3-carboxylicacid; and pharmaceutically acceptable derivatives thereof.
 11. Apharmaceutical formulation comprising a compound of claim 1 and one ormore pharmaceutically acceptable carrier.